Clinical research into the biology and treatment of acute leukemia is pursued with particular emphasis on acute lymphoblastic leukemia (ALL) of childhood. Major issues being addressed include: 1) development of therapeutic strategies aimed at improving overall prognosis of children with ALL, 2) investigation into the mechanisms of treatment failure with particular emphasis on evaluation of pharmacologic approaches to leukemic therapy, and 3) characterization of adverse sequelae of antileukemic therapy and design of treatment regimens which avoid them. An earlier ALL treatment protocol demonstrated that high-dose, protracted systemic methotrexate infusions could substitute for cranial radiation as central nervous system (CNS) preventive therapy for the majority of patients with ALL. Analysis of data from this study also identified a patient group at particular risk for CNS relapse. A new, high risk protocol has beer devised in an attempt to improve the prognosis for these and other poor risk patients. The results to date indicate that this therapy is highly effective in preventing both systemic and central nervous system relapses while avoiding the use of cranial radiation. In patients in the average risk category, a comparison of two forms of CNS preventive therapy (intrathecal vs High Dose Methotrexate) is under way. A major, multi-institutional pharmacologic monitoring protocol is in progress which is studying the relationship between the bioavailability of orally administered maintenance chemotherapy and relapse in children with ALL. On the basis of in vitro studies indicating that Interleukin-2 will induce phenotypic and functional maturation in acute lymphoblastic leukemia cells, a Phase I study of this potential antileukemic approach is being instituted. A study demonstrating expression of the 8 IL-2 receptor on hematopoietic malignant cells offers a potential avenue for future therapy. Detailed analysis of the immunologic and molecular phenotype of acute lymphoblastic leukemia has led to the concept of a hierarchy of differentiation for both T cell and pre-B cell ALL.